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Tumours and immune cells eat from the same plate. Cancer cells hoard glucose and glutamine, dump lactate and acid, and burn tryptophan and arginine into by-products that paralyse T cells. The tumour wins the food fight, and the immune system loses before it has fired a shot.
Glycolytic tumour cells deplete glucose, leaving T cells unable to sustain aerobic glycolysis needed for IFN-γ production (Chang et al. 2015); lactate export (MCT4) acidifies the niche, blocks T-cell lactate export and polarises macrophages to M2 (via GPR81, HIF-1α); hypoxia induces adenosine via CD39 → CD73, which signals through A2A receptors to suppress T and NK cells. IDO1 and TDO deplete tryptophan and produce kynurenine, activating AHR in T cells and Tregs (the IDO1 inhibitor epacadostat failed in ECHO-301 with pembrolizumab); arginase-1 from MDSCs and TAMs depletes arginine, which T cells need for proliferation; glutamine depletion and cysteine competition add to the exhaustion. Lipid-laden dendritic cells present antigen poorly. Countermeasures: A2A antagonists and CD73 antibodies (modest), arginase inhibitors, glutamine antagonists that spare T cells (DRP-104), metabolic engineering of CAR-T, and diet interventions in early trials.
A buffet where the tumour arrives first, eats the protein, and leaves the table sticky with lactate. The immune guests arrive hungry and find nothing but by-products that make them drowsy.
Shares Hypoxia-activated prodrugs, CSF1R, VHL / HIF oxygen sensing, HIF-2α and the tags mechanism, mechanics-atlas.
Shares Myeloid-derived suppressor cells (MDSCs), CSF1R, VHL / HIF oxygen sensing, HIF-2α and the tags mechanism, mechanics-atlas.
Shares IDO1, CSF1R, Myeloid suppression: TAMs, MDSCs & don't-eat-me signals, Tumour microenvironment (TME) and the tags mechanism, mechanics-atlas.
Shares Myeloid-derived suppressor cells (MDSCs), CSF1R, Myeloid suppression: TAMs, MDSCs & don't-eat-me signals, PD-1 and the tags mechanism, mechanics-atlas.
Shares Metabolic therapy: starving the tumour of a nutrient, Metabolic theory of cancer: from Warburg to oncometabolites, Cancer metabolism and the tags mechanism, mechanics-atlas.
Shares Armoured, logic-gated & next-gen CARs, Hot vs cold tumours, PD-1, Pembrolizumab and the tags mechanism, mechanics-atlas.
Shares IDO1, Hot vs cold tumours, VEGF / VEGFR, PD-1 and the tags mechanism, mechanics-atlas.
Shares Tumour microenvironment (TME), Hot vs cold tumours, Cold tumours and the immunosuppressive microenvironment, PD-1 and the tags mechanism, mechanics-atlas.